1. Field of the Invention
The invention relates to alleviation of symptoms of hypoxia resulting from reduced oxygen levels at high altitudes.
2. Summary of the Related Art
Hemoglobin is the oxygen transporter and regulator in blood. Each hemoglobin molecule can bind up to four oxygen atoms. The oxygen tension (in millimeters of mercury) at which the oxygen binding sites of hemoglobin are 50 percent saturated is called P50. P50 is inversely related to the binding affinity of hemoglobin for oxygen. Standard P50 is the P50 under standard conditions of 37° C., pH 7.4, carbon dioxide tension of 40 mm Hg at sea level, normally 26.3 mm Hg for a resting adult. However, important physiologic effects are determined by in vivo P50, which changes rapidly in responses to body temperature, carbon dioxide tension and pH.
As body temperature increases, the affinity of hemoglobin for oxygen decreases, raising the P50 and facilitating oxygen release. Lactic acidosis due to muscular activity further increases this effect. This is beneficial during prolonged heavy exercise. High levels of oxygen reduce P50 and increase the affinity of hemoglobin for oxygen. In contrast, low levels of oxygen increase P50 and decrease the affinity of hemoglobin for oxygen.
Taken together, these factors lead to a seriously decreased affinity of hemoglobin for oxygen under conditions of exercise at oxygen-depleted high altitudes. For example, at an altitude of 3,100 m a P50 of 29 mm Hg at rest and 38 mm Hg during heavy exercise have been observed. Thus, the primary limitation on oxygen transport at high altitude is impaired loading of oxygen onto hemoglobin caused by alveolar hypoxia.
Some animals indigenous to high altitudes, such as yaks, llamas and alpacas have high affinity hemoglobins having P50 about 10 mm Hg lower than in related lowland species due to amino acid substitutions in the globin chain. In fact, humans with the hemoglobin mutation Andrew-Minneapolis, resulting in a P50 of 17 mm Hg, have better physiologic function at high altitudes than normal subjects whose P50 is 26.3 mm Hg. However, as a result of having evolved at lower altitudes, most humans have an inappropriate increase of P50 at high altitudes, resulting in debilitating symptoms of hypoxia. There is no FDA approved drug that improves (lowers) the P50 and thus increases Hb affinity for oxygen in normal subjects. However, 5-HMF was evaluated for its effects on P50 in preclinical studies using sickle cell disease (SCD) red cells. These RBCs have a diminished oxygen carrying capacity due to amino acid changes in Hb structure as a result of a genetic mutation. Abdulmalik, Br. J. Haematol. 128:552-561 (2004), teaches that 5-HMF provides in vivo protection against the lethal effects of hypoxia in a sickle cell disease mouse model, and that this is the result of a lower P50 (left shift) in the SCD Hb, thus reducing the formation of sickled red blood cells in conditions of low oxygen in the inspired air. Thus, according to Abdumalik, the beneficial effect of 5-HMF in prolonging survival in the hypoxic state is due to the inhibition of RBC sickling, a phenomenon that is unique to SCD and would not be found in normal subjects. There is a need for new treatments for alleviating the symptoms of hypoxia in normal humans at high altitudes.